期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 9, 页码 8452-8463出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M412750200
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资金
- NCRR NIH HHS [P41-RR001395] Funding Source: Medline
- NICHD NIH HHS [KO8-HD45524, HD40793, HD08684] Funding Source: Medline
- NIDDK NIH HHS [DK38452, DK42956, DK57521, DK43351] Funding Source: Medline
The role of the actin cytoskeleton in regulating membrane protein trafficking is complex and depends on the cell type and protein being examined. Using the epididymis as a model system in which luminal acidification is crucial for sperm maturation and storage, we now report that modulation of the actin cytoskeleton by the calcium- activated actin- capping and - severing protein gelsolin plays a key role in regulating vacuolar H+ ATPase ( V- ATPase) recycling. Epididymal clear cells contain abundant V- ATPase in their apical pole, and an increase in their cell- surface V- ATPase expression correlates with an increase in luminal proton secretion. We have shown that apical membrane accumulation of VATPase is triggered by an elevation in cAMP following activation of bicarbonate- regulated soluble adenylyl cyclase in response to alkaline luminal pH ( Pastor- Soler, N., Beaulieu, V., Litvin, T. N., Da Silva, N., Chen, Y., Brown, D., Buck, J., Levin, L. R., and Breton, S. ( 2003) J. Biol. Chem. 278, 49523 - 49529). Here, we show that clear cells express high levels of gelsolin, indicating a potential role in the functional activity of these cells. When jasplakinolide was used to overcome the severing action of gelsolin by polymerizing actin, complete inhibition of the alkaline pH- and cAMP- induced apical membrane accumulation of V- ATPase was observed. Conversely, when gelsolin- mediated actin filament elongation was inhibited using a 10- residue peptide ( PBP10) derived from the phosphatidylinositol 4,5- bisphosphatebinding region ( phosphoinositide- binding domain 2) of gelsolin, significant V- ATPase apical membrane mobilization was induced, even at acidic luminal pH. In contrast, the calcium chelator 1,2- bis( 2- aminophenoxy) ethaneN, N, N', N'- tetraacetic acid tetrakis( acetoxymethyl ester) and the phospholipase C inhibitor U- 73122 inhibited the alkaline pH- induced V- ATPase apical accumulation. Thus, maintenance of the actin cytoskeleton in a depolymerized state by gelsolin facilitates calcium- dependent apical accumulation of V- ATPase in response to luminal pH alkalinization. Gelsolin is present in other cell types that express the V- ATPase in their plasma membrane and recycling vesicles, including kidney intercalated cells and osteoclasts. Therefore, modulation of the actin cortex by this severing and capping protein may represent a common mechanism by which these cells regulate their rate of proton secretion.
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